1. Field of the Invention
This invention relates to the treatment of thrombocythemia, secondary to myeloproliferative diseases, such as Essential Thrombocythemia (ET), Polycythemia Vera (PV), Chronic Myelogenous Leukemia (CML), and Other Myeloproliferative Diseases (OMPD) using an effective amount of the preferred active compound 2-amino-5,6-dichloro-3,4-dihydroquinazoline.
2. Description of Related Art
Anagrelide, which is chemically 6,7-dichloro-1,5-dihydroimidazo-[2,1-b]-quinazolin-2(3H)-one, is indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative diseases, such as Essential Thrombocythemia (ET), Polycythemia Vera (PV), Chronic Myelogenous Leukemia (CML), and Other Myeloproliferative Diseases (OMPD).
The formula for Anagrelide is: ##STR1##
The major clinical action of Anagrelide is to decrease and maintain the platelet count within normal limits. The most common adverse effects associated with the use of Anagrelide are related to its vasodilatory and positive inotropic effects. Cardiovascular side effects associated with the use of Anagrelide have included: vasodilation (&lt;5%), tachycardia (7.5%), palpitations (26.1%), and congestive heart failure (1.5%).
A study by Gaver et al. (1981) "Clinical Pharmacology and Therapeutics", 29, 381-392, demonstrated that Anagrelide was extensively metabolized by human subjects to a minimum of at least four to five compounds excreted in the urine and that peak plasma concentrations of the parent drug were only 6 ng/mL. It was reported that very little of the Anagrelide dose (&lt;1%) was excreted as unchanged drug in the urine. These studies raised the possibility that the thromobocytopenia observed with Anagrelide may be due to a metabolite rather than the parent drug. In the Gaver study the use of .sup.14 C-anagrelide indicated by HPLC a minimum of four to five metabolites which accounted for over 75% of the urinary radioactivity. It was concluded that the antiaggregation activity observed in humans is possibly related to the presence of Anagrelide and an active metabolite(s).
U.S. Pat. No. 3,932,407 and its Reissue Pat. No. Re. 31,617, which patents are hereby incorporated by reference, disclose Anagrelide type compounds of the formula: ##STR2##
in which R.sup.1 is H, phenyl or lower alkyl, R.sup.2 and R.sup.3 when alike are H, chloro, bromo, fluoro, lower alkyl, hydroxy or lower alkoxy, R.sup.2 and R.sup.3 when different are H, chloro, bromo, fluoro, SO.sub.3 H, CF.sub.3, hydroxy, nitro, amino, phenyl, lower alkyl of 1 to 3 carbon atoms or lower alkoxy of 1 to 3 carbon atoms, or when taken together R.sup.2 and R.sup.3 are methylenedioxy or the residue of phenyl ring, and n is an integer of 1 or 2; and pharmaceutically acceptable acid addition salts thereof. The compounds, which are disclosed as hypotensive, blood platelet reducer and/or bronchodilator agents, are prepared inter alia by a multistep process ending in the reaction of CNBr with an ethanol solution of a compound of the formula: ##STR3##
in which R.sup.1, R.sup.2, R.sup.3 and n are as described above, and R.sup.4 is lower alkyl.
Anagrelide having the chemical name 6,7-dichloro-1,5-dihydroimidazo[2.1-b]quinazolin-2[3H]-one and the structural formula shown as (A) above is of particular interest because it is known to be a potent reducer of platelet count induced by a variety of aggregating agents.
Anagrelide may be prepared directly from a lower alkyl-N-(6-amino-2,3-dichlorobenzyl)glycine of Formula (C) by reaction in an alcoholic solution with CNBr. U.S. Pat. No. 4,146,718 incorporated herein by reference, discloses an improved process whereby higher yields of Anagrelide may be obtained by reacting a compound of Formula (C) with, for example, CNBr, CNCl or CNI in an inert, aprotic organic solvent and isolating the novel intermediate of Formula D. ##STR4##
wherein R.sup.4 is (lower)alkyl and X is chloro, bromo or iodo. In a preferred embodiment X is bromo and R.sup.4 is methyl, ethyl, n-propyl, isopropyl or n-butyl. In a more preferred embodiment X is bromo and R.sup.4 is methyl, ethyl or n-propyl. In a most preferred embodiment X is bromo and R.sup.4 is ethyl.
Intermediate Compound (D) is then treated with a base to produce the Anagrelide compound of Formula A.
As reported in U.S. Pat. No. 4,146,718, supra, although the compounds of Formula (D) are primarily intended as intermediates in the preparation of Anagrelide, they themselves have blood platelet antiaggregative properties.
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a compound which has enhanced platelet reducing properties without side effects of presently used compounds such as Anagrelide.
It is another object of the present invention to provide a method for making a compound having enhanced platelet reducing properties.
A further object of the invention is to provide a method for reducing the platelet count in a patient by administering a platelet reducing amount of a compound having enhanced platelet reducing properties preferably with a pharmaceutical carrier in a unit dose.
It is yet another object of the present invention to provide a pharmaceutical composition containing a compound effective for reducing the platelet count together with pharmaceutically acceptable excipients.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specification.